N-Substituted phthalimides are useful intermediates for the synthesis of a large variety of primary amines via well-known processes such as the Gabriel synthesis (e.g., Gibson et al., Angew. Chem. Int. Ed. Engl., 1968, 7, 919) and Ing-Manske procedure (Ing et al., J. Chem. Soc., 1926, 2348).
N-Substitution of phthalimides can be mediated by the versatile Mitsunobu reaction (Mitsunobu et al., Bull. Chem. Soc. Jpn., 1967, 40, 2380; Camp et al., Aust. J. Chem., 1988, 41, 1835) the general outline of which is shown below in Scheme I. This reaction typically utilizes a triarylphosphine and a dialkyl azodicarboxylate as reactants, which serve to activate a primary or secondary alcohol towards nucleophilic attack by acidic or weakly acid groups such as phenols, carboxylic acids, diimides, etc. While the Mitsunobu reaction is a versatile synthetic tool since it allows one to directly activate and substitute an alcohol group in one step, it has the drawback of generating the undesirable by-products of triphenylphosphine oxide and a dialkyl, diacyl hydrazide in stoichiometric amounts. These reaction by-products, in addition to any unreacted reagents can often lead to difficult or tedious separations, thus potentially limiting the industrial utility of the process.

As can be well appreciated by the skilled artisan, the N-substituted phthalimides are widely useful in all areas of synthetic chemistry and particularly pharmaceutical research. For example, 2-(3-butynyl)-1-H-isoindole-1,3-(2H)-dione is used in the preparation of pain relieving drugs that are inhibitors of the enzyme cytosolic phospholipase A2 as reported in, for example WO 03/048122A2. Preparations of this intermediate via Mitsunobu and other reactions have also been reported in Griffiths et al., Tetrahedron, 1992, 48, 5543; Jackson et al., Aust. J. Chem., 1988, 41, 1201; Acta. Pharm. Suec., 1975, 12, 290; Jackson et al., Tetrahedron, 1988, 29, 1983; Hoffmann et al., J. Med. Chem., 1975, 18, 278; NL 6600916; NL 6501131; and Iyer et al., J. Am. Chem. Soc., 1987, 109, 2759. These preparations, however, tend to involve multistep syntheses, commercially unavailable starting materials, lengthy reaction times, chlorinated solvent, and/or complicated isolation or purification steps. Accordingly, improved synthetic routes to N-substituted phthalimides are needed, and the processes described herein help meet this and other needs.